The Role of Epigenetics in Mitochondrial Biogenesis-Mediated Recovery after Spinal Cord Injury

表观遗传学在脊髓损伤后线粒体生物发生介导的恢复中的作用

• 批准号: 10216171
• 负责人: Natalie E Scholpa
• 金额: --
• 依托单位: SOUTHERN ARIZONA VA HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10216171
• 关键词: ADRB2 gene; Address; Adrenergic Agonists; Affect; Age; Agonist; Antioxidants; Area; Behavioral; Biogenesis; Bioinformatics; Biology; Blood Vessels; Caring; Cell physiology; Clinical; Clinical Trials; Communication; Complex; Data; Development; Development Plans; Devices; Disease; Doctor of Philosophy; Epigenetic Process; Event; Exposure to; FDA approved; Female; Financial compensation; Functional disorder; Gene Expression Profiling; Genes; Genetic; Genetic Transcription; Genomics; Goals; Health Care Costs; Healthcare; Healthcare Systems; Human; Individual; Injury; Intensive Care; Investigation; Knowledge; Laboratories; Lesion; Locomotor Recovery; Maintenance; Mediating; Mediator of activation protein; Medical; Mentors; Mitochondria; Modification; Molecular; Mus; Nature; Neurosurgeon; Oral; Oxygen; Pathology; Patients; Pharmacology; Phase; Play; Publishing; Recovery; Rehabilitation therapy; Reporting; Research Personnel; Role; Site; Spinal Cord; Spinal cord injury; Therapeutic; Time; Training; Trauma; United States; United States Department of Veterans Affairs; Veterans; beta-2 Adrenergic Receptors; career; career development; clinical application; cost; disability; educational atmosphere; epigenome; experience; formoterol; improved; in vivo; injury recovery; innovation; loss of function; male; mitochondrial dysfunction; novel strategies; prevent; service member; skills; therapeutic target; treatment group

The goal of this project is to determine the role of epigenetic modifications of mitochondrial genes in the induction of the plateau phase after spinal cord injury (SCI), and to exploit these modifications to promote recovery. SCI is a devastating disorder often resulting in loss of function below the injury site. In recent years, service members have been threatened by more advanced warfare, such as improvised explosive devices, ultimately inducing more severe and complex injuries, including SCI. The devastating and debilitating nature of these injuries has not been lessened. The Department of Veterans Affairs (VA) is the largest healthcare network for individuals suffering from SCI, providing care for 25% of total victims in the United States. Improved therapeutics for the treatment of SCI would greatly benefit not only sufferers, but also the VA healthcare system. SCI is defined by direct trauma to the spinal cord, which disrupts the vasculature, leading to decreased oxygen delivery within the area and reducing the ability of mitochondria to maintain cellular energetics. Thus far, the majority of studies targeting mitochondrial dysfunction following SCI have focused on downstream aspects of mitochondrial function (e.g. antioxidant defenses). Reestablishment of mitochondrial function through pharmacological induction of mitochondrial biogenesis (MB) remains an underexplored but novel strategy. I previously reported that treatment with the mitochondrially biogenic FDA-approved β2-adrenergic receptor agonist formoterol beginning up to 8h after SCI improves spinal cord mitochondrial function, decreases lesion volume and enhances locomotor recovery by 7 days post-injury (DPI). Consistent with other published data, the majority of the improvements observed with formoterol occurred within the first 2 weeks, after which recovery plateaued. A similar effect is observed in humans, with the majority of recovery taking place within the first year then reaching a plateau. The mechanism behind the development of this plateau phase, however, is not fully understood. By determining the mechanism of its formation, the plateau phase could be prevented and/or reversed, potentially allowing for continued recovery following injury. My preliminary studies revealed genetic differences within the injured spinal cord of formoterol-treated mice between the recovery phase (7 DPI) and the plateau phase (15 DPI), namely a decrease in genes associated with mitochondrial function, and a concurrent increase in genes associated with epigenetic modifications. Therefore, I hypothesize that epigenetic alterations contribute to decreased transcription of mitochondrial genes within the spinal cord during the plateau phase, preventing continued recovery of mitochondrial function and limiting the efficacy of formoterol treatment in mice. To address this hypothesis, I propose the following Specific Aims: 1) Further elucidate the genetic profile within the spinal cord during the post-SCI recovery period (7 DPI) and plateau phase (≥15 DPI), with and without formoterol treatment in mice; 2) Elucidate the mechanisms of epigenetic modifications on the transcription of mitochondrial genes during the transition from recovery to plateau phase post-SCI, with and without formoterol treatment; 3) Assess the pharmacological efficacy of inhibiting epigenetic events on MB and recovery post-SCI in vivo, with and without formoterol treatment. Successful completion of this proposal could provide integral information into the recovery plateau observed after SCI. I am using an FDA-approved compound, male and female mice and initiating treatment up to 8h after injury, emphasizing the clinical applicability. This proposal will also directly assess the therapeutic potential of my findings by determining if modulation of epigenetic status improves recovery after injury. My mentoring team has formulated a comprehensive career development plan that includes exposure to a rich educational environment, opportunities to improve oral and written communication skills and mentoring on project and laboratory maintenance to ease transition to independence. This project and training will facilitate the completion of my long-term career goal of becoming and independent VA researcher.

该项目的目标是确定线粒体基因的表观遗传修饰在 诱导脊髓损伤（SCI）后的平台期，并利用这些修改， 促进复苏。SCI是一种破坏性的疾病，通常会导致损伤部位以下的功能丧失。近几 多年来，服役人员一直受到更先进的战争的威胁，如简易爆炸装置， 器械，最终导致更严重和复杂的损伤，包括SCI。毁灭性的和衰弱的 这些伤害的性质并没有减轻。退伍军人事务部（VA）是美国最大的医疗保健机构。 该网络为SCI患者提供服务，为美国25%的受害者提供护理。改进 用于治疗SCI的治疗方法将不仅极大地有益于患者，而且有益于VA保健系统。 SCI的定义是脊髓的直接创伤，破坏了血管系统，导致氧气减少 在该区域内递送并降低线粒体维持细胞能量的能力。到目前为止， 大多数针对SCI后线粒体功能障碍的研究都集中在 线粒体功能（例如抗氧化防御）。线粒体功能的重建 线粒体生物发生（MB）的药理学诱导仍然是一种未充分探索但新颖的策略。 我以前报道过，用FDA批准的生物源性β2-肾上腺素能受体治疗， SCI后8小时开始使用激动剂福莫特罗可改善脊髓线粒体功能，减少损伤 在损伤后7天（DPI），体积和增强运动恢复。与其他公布的数据一致， 福莫特罗组观察到的大部分改善发生在前2周内，之后恢复 稳定下来了在人类中也观察到类似的效果，大多数恢复发生在第一年内 然后达到一个平台期。然而，这一平台期发展背后的机制并不完全清楚。 明白通过确定其形成的机制，可以防止平台期和/或 逆转，可能允许受伤后继续恢复。我的初步研究显示 福莫特罗治疗小鼠的脊髓损伤在恢复期（7 DPI）和恢复期（7 DPI）之间的差异 平台期（15 DPI），即与线粒体功能相关的基因减少，同时 与表观遗传修饰相关的基因增加。因此，我假设表观遗传 改变有助于减少脊髓内线粒体基因的转录， 平台期，阻止线粒体功能的持续恢复，并限制 福莫特罗治疗小鼠。为了解决这一假设，我提出了以下具体目标：1）进一步 阐明SCI后恢复期（7 DPI）和平台期脊髓内的遗传特征 （≥15 DPI），有和没有福莫特罗治疗的小鼠; 2）阐明表观遗传的机制， 从恢复期向平台期过渡期间线粒体基因转录的改变 SCI后，有和没有福莫特罗治疗; 3）评估抑制表观遗传的药理学疗效， 在有和没有福莫特罗治疗的情况下，体内MB事件和SCI后恢复。 成功完成该提案可以为观察到的恢复平台期提供完整的信息 SCI之后我正在使用FDA批准的化合物，雄性和雌性小鼠，并在治疗后8小时开始治疗。 损伤，强调临床适用性。该提案还将直接评估 我的发现是通过确定表观遗传状态的调节是否能改善损伤后的恢复。 我的指导团队制定了一个全面的职业发展计划，其中包括接触丰富的 教育环境，提高口头和书面沟通技能的机会， 项目和实验室维护，以便于向独立过渡。该项目和培训将促进 完成我的长期职业目标，成为独立的退伍军人事务研究员。